Our Research
Some rules of the immune system are symbolically akin to the laws of physics. "For every action, there is an equal and oppositive reaction" applies similarly to the human immune system, perhaps evolved to be peace-keepers even more so than soldiers that attack foreign invaders. As such, it has enumerable non-redundant mechanisms to suppress aberrant immune attacks on self-tissues after a pathogen is defeated and restore the body back to homeostasis. The problem with cancer is not only that tumor cells can look similar to the body's normal cells, but it can also survive under the protection of the immune system's potent tolerogenic programming. Certain organ sites, such as the liver, appear to have evolved to have more tolerogenic property than others. The liver's unique property allows it to act as a sophisticated first-pass filter and immune regulator for the myriad of ingested foreign proteins and gut microbiome antigens. Interestingly, when compared to other anatomical metastatic sites, liver metastasis was correlated with reduced response rate, progression-free and overall survival in not only melanoma but most metastatic solid cancer patients treated with CPIs. Preclinical studies suggest that the liver is a potent immunoregulatory organ, and liver metastasis is associated with deleterious systemic tumor-specific T cell dysfunction that is not reversible with CPIs. Using this powerful regulatory organ as a model to study the tolerogenic impacts of metastasis, we are beginning to discover new rules of tumor immunity in the context of immunotherapy, which we hope can lead to more effective treatments that can break tumor-immune tolerance with more precision and potency.
Active Lab Projects:
1) Parallel preclinical and clinical profiling of the molecular pathways driving the tolerogenic liver metastatic tumor-liver stromal interface using next-generation, A.I. assisted, spatially-resolved multiomic analysis.
2) Studying the effects of neoadjuvant checkpoint inhibitor + metastatic-site surgery or radiotherapy on liver metastasis resistance and methods to generate therapeutic synergy.
3) Testing and learning from other clinically challenging metastatic sites to discover similar or new mechanisms of tolerance.
